Endocrine Resistance in Breast Cancer

Around 70% of all breast cancers are estrogen receptor alpha positive and hence their development is highly dependent on estradiol. While the invention of endocrine therapies has revolusioned the treatment of the disease, resistance to therapy eventually occurs in a large number of patients. This paper seeks to illustrate and discuss the complexity and heterogeneity of the mechanisms which underlie resistance and the approaches proposed to combat them. It will also focus on the use and development of methods for predicting which patients are likely to develop resistance. 1. Introduction Approximately 70% of breast cancers are considered estrogen receptor alpha (ER ) and/or progesterone receptor (PR) positive, and the hormone estrogen (17β-estradiol, E2) represents the primary stimulant in the growth and development of these tumours [1]. Thus deprivation of estrogen signalling through endocrine-targeted therapy has become the mainstay of treatment in ER -positive disease. Despite the benefits, endocrine therapy resistance eventually occurs in a large number of patients and represents a significant issue for optimal clinical management [2]. In recent years a large body of work has focused on trying to understand the underlying mechanisms leading to resistance and approaches for their circumvention, as well as developing methods to predict which patients are likely to develop resistance and are therefore in need of additional or alternative therapies. While numerous mechanisms have been proposed in addition to those discussed in this review, a major lesson from the laboratory has been the realisation that resistance is both highly complex and heterogeneous and it is clear that more work is needed to identify and improve clinical outcome of patients with ER-positive breast cancers. 2. Estrogen Production In both pre- and postmenopausal woman estrogen production occurs locally in the normal tissues of subcutaneous fat, the breast, muscle tissue and bone, where it is produced by the enzymatic conversion of androgens (androstenedione and testosterone) by aromatase [1, 3–8] (Figure 1). Within breast cancer tissue, expression of aromatase occurs mainly in fibroblasts [9]. Residual levels of estrogen are also commonly found circulating in the blood and are around 20-fold higher in postmenopausal women compared with premenopausal women, despite the loss of ovarian estrogen production [4, 5, 10]. In postmenopausal women there is a noticeable correlation between risk of breast cancer and levels of circulating estrogen in the blood plasma [11]. Aromatase